Chronic use of cocaine in humans results in long-lasting alterations in brain structure and function. In laboratory animals, repeated intermittent cocaine administration produces an augmented behavioral response to a subsequent challenge dose of the drug. This phenomenon, referred to as behavioral sensitization, may be important in cocaine craving, a central factor in many cases of drug relapse. The endogenous opioid peptide/receptor system has been implicated in cocaine sensitization. However, the role of the OFQ/N/ORL-1 receptor system has not been characterized in this phenomenon. Our preliminary data show that concomitant OFQ/N administration with cocaine blocks the development of cocaine sensitization and this action of OFQ/N is antagonized by J-113397, an ORL-1 receptor antagonist. Thus, the OFQ/N/ORL-1 receptor system plays an important role in blocking this phenomenon and may be a potential target to develop drugs with anti-craving activity. In order to characterize the neurobiological substrate for such an action of OFQ/N, we will elucidate the site of action of OFQ/N. Additionally, since OFQ/N or related drugs will be used to treat cocaine addicts, using sensitization as an animal model of drug craving, we will determine if OFQ/N could reverse an already existing sensitized response, a more clinically relevant issue. Our preliminary data also show that the level of hypothalamic OFQ/N increases after repeated cocaine treatment, indicating that the endogenous OFQ/N/ORL-1 receptor system may be altered during development of sensitization. Thus, using RIA and binding assays, we will measure levels of OFQ/N and its receptor after cocaine treatment in brain regions involved in cocaine craving. Using knockout mice, we will also study the development of sensitization in the absence of the ORL-1 receptor or OFQ/N. The studies proposed in this grant will elucidate the role of OFQ/N/ORL-1 receptor system in cocaine sensitization and possibly provide important and useful information toward developing possible treatments for cocaine addiction.